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This review highlights recent advances in atopic dermatitis (AD) and food allergy (FA), particularly on molecular mechanisms and disease endotypes, recent developments in global strategies for the management of patients, pipeline for future treatments, primary and secondary prevention and psychosocial aspects. During the recent years, there has been major advances in personalized/precision medicine linked to better understanding of disease pathophysiology and precision treatment options of AD. A greater understanding of the molecular and cellular mechanisms of AD through substantial progress in epidemiology, genetics, skin immunology and psychological aspects resulted in advancements in the precision management of AD. However, the implementation of precision medicine in the management of AD still requires the validation of reliable biomarkers, which will provide more tailored management, starting from prevention strategies towards targeted therapies for more severe diseases. Cutaneous exposure to food via defective barriers is an important route of sensitization to food allergens. Studies on the role of the skin barrier genes demonstrated their association with the development of IgE-mediated FA, and suggest novel prevention and treatment strategies for type 2 diseases in general because of their link to barrier defects not only in AD and FA, but also in asthma, chronic rhinosinusitis, allergic rhinitis and inflammatory bowel disease. The development of more accurate diagnostic tools, biomarkers for early prediction, and innovative solutions require a better understanding of molecular mechanisms and the pathophysiology of FA. Based on these developments, this review provides an overview of novel developments and advances in AD and FA, which are reported particularly during the last two years., (Copyright © 2019 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.) more...

Niacin, also known as vitamin B3, is required for the synthesis of coenzymes, nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP). Niacin binds with G protein-coupled receptor (GPR) 109A on cutaneous Langerhans cells and causes vasodilation with flushing in head and neck area. Niacin deficiency due to excessive alcohol consumption, certain drugs or inadequate uptake in diet causes pellagra, a photosensitivity dermatitis. Recently several studies have revealed the mechanism of photosensitivity in niacin deficiency, which may pave a way for new therapeutic approaches. The expression level of prostaglandin E synthase (PTGES) is up-regulated in the skin of both pellagra patients and niacin deficient pellagra mouse models. In addition, pellagra is mediated through prostaglandin E₂-EP4 (PGE₂-EP4) signaling via reactive oxygen species (ROS) production in keratinocytes. In this article, we have reviewed the role of niacin in immunity and the mechanism of niacin deficiency-induced photosensitivity. more...

Approximately 50% of patients with adult T-cell leukemia/lymphoma (ATLL) have skin involvement, and the smoldering, skin lesion-bearing cases are often treated with various skin-directed therapies, such as phototherapy and radiation therapy. Daily oral administration of etoposide plus prednisolone (EP) is also used for smoldering-type ATLL. However, it remains unclear whether these therapies improve patients' survival. We retrospectively analyzed the prognosis of patients with smoldering, skin lesion-bearing ATLL (n = 62), who were treated, as first therapy, with one skin-directed therapy (n = 29), oral EP alone (n = 14) or a combination of skin-directed therapy and oral EP (n = 19). Multivariate analysis revealed that the hazard ratios (HRs) for the overall survival (OS) and progression-free survival (PFS) with the combination therapy were significantly lower than those with the skin-directed therapy (HR 0.1, p = 0.001; HR 0.2, p = 0.002, respectively). These results suggest that the combination of skin-directed therapy and oral EP improves the clinical outcome of patients with smoldering, skin lesion-bearing ATLL. more...

Background: Atopic dermatitis (AD) can be classified into the major extrinsic type with high serum IgE levels and impaired barrier, and the minor intrinsic type with normal IgE levels and unimpaired barrier., Objective: To characterize the intrinsic type of Japanese AD patients in the T helper cell polarization in relation to the barrier condition., Methods: Enrolled in this study were 21 AD patients with IgE<200kU/L (IgE-low group; 82.5±59.6kU/L) having unimpaired barrier, and 48 AD patients with IgE>500kU/L (IgE-high group; 8.050±10.400kU/L). We investigated filaggrin gene (FLG) mutations evaluated in the eight loci common to Japanese patients, circulating Th1, Th2 and Th17 cells by intracellular cytokine staining and flow cytometry, and blood levels of CCL17/TARC, IL-18, and substance P by ELISA., Results: The incidence of FLG mutations was significantly lower in the IgE-low group (10.5%) than the IgE-high group (44.4%) (normal individuals, 3.7%). The percentage of IFN-γ-producing Th1, but not Th2 or Th17, was significantly higher in the IgE-low than IgE-high group. Accordingly, Th2-attracting chemokine CCL17/TARC, was significantly lower in the IgE-low than the IgE-high group. There were no differences between them in serum IL-18 levels, or the plasma substance P levels or its correlation with pruritus., Conclusion: The IgE-low group differed from the IgE-high group in that it had much less FLG mutations, increased frequency of Th1 cells, and lower levels of CCL17. In the intrinsic type, non-protein antigens capable of penetrating the unimpaired barrier may induce a Th1 eczematous response., (Copyright © 2012 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.) more...

Cutaneous involvement is seen in ~ 50% of adult T-cell leukemia/lymphoma (ATLL) patients. We investigated the association between skin eruption type and prognosis in 119 ATLL patients. ATLL eruptions were categorized into patch (6.7%), plaque (26.9%), multipapular (19.3%), nodulotumoral (38.7%), erythrodermic (4.2%), and purpuric (4.2%) types. When the T stage of the tumor-node-metastasis-blood (TNMB) classification of mycosis fungoides/Sézary syndrome was applied to ATLL staging, 16.0% were T1, 17.7% T2, 38.7% T3, and 4.2% T4, and the remaining 23.5% were of the multipapular and purpuric types. For the patch type, the mean survival time (median survival time could not be estimated) was 188.4 months. The median survival times (in months) for the remaining types were as follows: plaque, 114.9; multipapular, 17.3; nodulotumoral, 17.3; erythrodermic, 3.0; and purpuric, 4.4. Kaplan-Meier curves of overall survival showed that the erythrodermic type had the poorest prognosis, followed by the nodulotumoral and multipapular types. The patch and plaque types were associated with better survival rates. Multivariate analysis demonstrated that the hazard ratios of the erythrodermic and nodulotumoral types were significantly higher than that of the patch type, and that the eruption type is an independent prognostic factor for ATLL. The overall survival was worse as the T stage became more advanced: the multipapular type and T2 were comparable, and the purpuric type had a significantly poorer prognosis than T1. more...

Eosinophilia in the blood and skin is frequently observed in patients with certain inflammatory skin diseases, such as atopic dermatitis. However, the mechanism underlying eosinophil circulation and the role of eosinophils in cutaneous immune responses remain unclear. In repeated hapten application-induced cutaneous responses in BALB/c mice, the administration of FTY720 before the last challenge decreased the number of skin-infiltrating eosinophils and reduced the late-phase reaction. A similar reduction of the late-phase reaction was observed by a sphingosine-1-phosphate G protein-coupled receptor (S1P1)-selective agonist, SEW2871. We monitored numerous alterations of eosinophils in the blood, spleen, bone marrow, and lymph nodes of interleukin-5 transgenic mice, used as an eosinophilia model, following FTY720 administration. The number of circulating eosinophils was significantly decreased after treatment with FTY720, and eosinophils accumulated in the bone marrow. In addition, eosinophils expressed S1P1, S1P3, and S1P4 mRNAs, and their chemotactic response to S1P was abolished by FTY720 as well as by SEW2871. These findings suggest that FTY720 affects the number of eosinophils in both the blood and skin by inhibiting the egress of eosinophils from the bone marrow and thus downmodulating the late-phase reaction. more...

Nitric oxide (NO) has several important roles in various physiological settings; one of the NO synthases, inducible NO synthase (iNOS), is induced by external stimulation of the skin. A prototypic example of external stimulation is hapten exposure, which induces the T-cell-mediated immune response known as contact hypersensitivity (CHS). We herein report on cutaneous dendritic cell (DC) function in the presence of an iNOS-specific inhibitor during the sensitization phase of CHS. First, we examined epidermal cell (EC) suspensions using flow cytometry with an iNOS antibody and confirmed that iNOS was expressed in the cytoplasm of Langerhans cells (LCs). We then studied the role of iNOS in CHS, and found that responses to DNFB were enhanced by the addition of an iNOS inhibitor during sensitization. Similarly, the iNOS inhibitor augmented FITC-induced migration of cutaneous DCs, including Langerin(+) LCs and Langerin(-) dermal DCs, to draining lymph nodes. Finally, we showed that iNOS inhibitor enhanced LC survival in vitro. We concluded that NO suppresses migration and survival of cutaneous DCs, resulting in a downmodulation of CHS. more...

CCR7 is regarded as an essential chemokine receptor for cutaneous dendritic cell (DC) migration into the regional lymph nodes. However, complete migratory inhibition cannot be obtained in CCR7-deficient mice, suggesting that there exist other chemokine receptors involved in this process. Initially, we found that CXCR4 was highly expressed on migrated cutaneous DCs and that its ligand, CXCL12, was detected in the LYVE-1(+) lymphatic vessels in the skin. FITC-induced cutaneous DC migration into the draining lymph nodes was impaired by the specific CXCR4 antagonist 4-F-Benzoyl-TN14003. Among FITC(+) cells, Langerin(+) Langerhans cells and Langerin(-) (dermal) dDC subsets were detected as CD11c(high+)CD11b(int+) cells and CD11c(high+)CD11b(high+) plus CD11c(low+)CD11b(int+) cells, respectively, both of which were suppressed by CXCR4 antagonist. Moreover, in vivo contact hypersensitivity response was impaired by CXCR4 antagonist administered during the sensitization phase. The in vitro proliferative response to dinitrobenzene sulfonic acid of sensitized lymph node cells was inhibited by CXCR4 antagonist treatment. These findings demonstrated that CXCL12-CXCR4 engagement on cutaneous DCs plays a crucial role in the initiation of skin immune response by enhancing cutaneous DC migration. more...

Human type 2 innate lymphoid cells disrupt skin keratinocyte tight junction barrier by IL-13 C, mRNA expression of tight junction (TJ) genes cocultured with ILC2s. To further investigate skin keratinocyte TJ barrier by ILC2s, we analyzed the mRNA expression of TJ and related genes by quantitative PCR. As shown in Figure S4, NHEKs exposed to IL-13 showed significantly lower TER compared with unstimulated NHEKs, suggesting that IL-13 recapitulates the decreased barrier integrity by ILC2-derived IL-13. [Extracted from the article] more...

The article presents a case study of a 23-year-old Japanese female with cerebral palsy due to neonatal asphyxia, who had never walked, presented with a 10-year history of a slowly enlarging pigmented lesion on the lateral plantar surface of the left foot. It discusses the Histopathological examination revealed naevus cell nests located in the epidermal rete ridges and dermoscopic features of a melanocytic naevus on plantar skin include parallel furrow, lattice-like and fibrillar patterns. more...

The article presents a case study of a 76‑year‑old Japanese woman was initially referred to us in 2003 for evaluation of a 4‑year history of skin eruption. Topics include the eruption first appeared as generalized patches and plaques, the skin biopsy specimen from erythematous plaque disclosed numerous atypical lymphocytes in the dermis with their epidermotropism, and the presence of epithelioid cells associated with mixed inflammatory infiltrate such as neutrophils and eosinophils. more...